SUMMARY OF WORK: PURPOSE: Eight years ago, I proposed a new model of the immune system (the Danger model) based on the assumption that the immune system's function is to discriminate between dangerous and harmless things rather than self and non-self. Because this model has tremendous implications for such subjects as cancer, transplantation, neonatal and adult vaccines, parasitology, and autoimmunity, we have been testing its basic premises and its applicability in several areas. RESULTS FROM THE PAST YEAR: 1) PARASITES AND BACTERIA: We found that A) dead bacteria cause the activation of antigen presenting cells but living bacteria do not B) Living Leishmania do not activate dendritic cells C) the reason that Leishmania cause different diseases in different strains of mice is because the parasites traffic to different areas in the body of those mice. 2) TOLERANCE (in PREGNANCY and HEMOPHILIA: A) oral administration of Factor VIII or factor IX induces immunological tolerance and corrects the bleeding time in hemophiliac mice. 3) T CELLS: A) naive and memory T cells do not need MHC molecules for survival or the initiation of homeostatic division. B) Memory T cells communicate with naive T cells via a dendritic cell, by educating the dendritic cell to pass on the appropriate messages. C) Killer T cells can reject skin grafts that they cannot recognize. 4) DENDRITIC CELLS: A) canine dendritic cells can be isolated from blood and cultured in vitro using conditions similar to mouse dendritic cells. B) dendritic cells from TLR4 KO mice can be activated by LPS if wild type dendritic cells are present in the same well.